Diverse progenitor cells preserve salivary gland ductal architecture after radiation-induced damage.

The ductal system of the salivary gland has long been postulated to be resistant to radiation-induced damage, a common side effect incurred by head and neck cancer patients receiving radiotherapy. Yet, whether the ducts are capable of regenerating after genotoxic injury, or whether damage to ductal cells induces lineage plasticity, as has been reported in other organ systems, remains unknown. Here, using the murine salivary gland, we show that two ductal progenitor populations, marked exclusively by KRT14 and KIT, maintain non-overlapping ductal compartments after radiation exposure but do so through distinct cellular mechanisms. KRT14+ progenitor cells are fast-cycling cells that proliferate in response to radiation-induced damage in a sustained manner and divide asymmetrically to produce differentiated cells of the larger granulated ducts. Conversely, KIT+ intercalated duct cells are long-lived progenitors for the intercalated ducts that undergo few cell divisions either during homeostasis or after gamma radiation, thus maintaining ductal architecture with slow rates of cell turnover. Together, these data illustrate the regenerative capacity of the salivary ducts and highlight the heterogeneity in the damage responses used by salivary progenitor cells to maintain tissue architecture.

Impact of postoperative radiotherapy and HER2/new overexpression in salivary duct carcinoma : A monocentric clinicopathologic analysis.

AIM: Retrospective Investigation of the prognostic relevance of clinicopathologic parameters in patients with salivary duct carcinoma (SDC). METHODS: An experienced pathologist reviewed 67 patients with de novo SDC or SDC ex pleomorphic adenoma. Paraffin-embedded tumor samples were examined by immunohistochemistry for expression of HER2/neu, androgen (AR), progesterone (PR), estrogen (ER), epidermal growth factor (EGFR) and programmed death ligand 1 (PD-L1-R) receptor. In 45 patients who had cM0 and follow-up data available, survival rates were calculated (Kaplan-Meier method) and prognostic variables were analyzed (univariate analysis: log-rank test; multivariate analysis: Cox-regression analysis). RESULTS: Overexpression of HER2/neu, AR, ER, PR, EGFR, PD-L1-R was found in 25.4%, 84%, 0%, 0%, 17.9%, 16.4% of patients. Overall (OS), disease-free (DFS), distant-metastases-free survival (DMFS) and locoregional control (LRC) were 92.3/72.4/56.9%, 78.2/58.1/58.1%, 85.4/65.2/65.2% and 89.7/81.9/81.9% after 1/3/5 years (medial follow-up 26 months). In univariate analysis a positive resection margin (p = 0.008) and no postoperative radiotherapy (p = 0.001) predict an increased locoregional recurrence rate. In multivariate analysis only postoperative radiotherapy is statistically significant (p = 0.004). Presence of lymph node metastases, a lymph node density >4 and HER2/neu overexpression predict decreased DFS and DMFS. In multivariate HER2/neu overexpression was the only significant predictor for reduced DFS (p = 0.04) and DMFS (p = 0.02). CONCLUSION: Postoperative radiotherapy is the only significant predictor for LRC. HER2/neu receptor expression is an independent prognostic factor for decreased DFS and DMFS in patients with SDC. In addition to radio(chemo)therapy, intensified first-line treatment regimens should also be evaluated in the future.

Sialendoscopy-assisted treatment for radioiodine-induced sialadenitis.

PURPOSE: Chronic sialadenitis is a common complication of radioactive iodine for the treatment of thyroid disease. The aim of this study was to describe the authors' experience with interventional sialendoscopy for the management of radioiodine-induced sialadenitis. MATERIALS AND METHODS: Twelve patients with radioiodine-induced sialadenitis treated with sialendoscopy from January 2013 through December 2013 at the Department of Oral and Maxillofacial Surgery, School of Stomatology, China Medical University were retrospectively reviewed. Age, gender, and time to development of radioiodine-induced sialadenitis were obtained from the hospital database. All patients were asked to undergo visual analog scale (VAS) and salivary gland scintigraphy (SGS) examinations before and 6 months after surgery. A paired t test was conducted, and a P value less than .05 was considered statistically significant. RESULTS: Twelve patients (15 parotid glands and 4 submandibular glands) successfully underwent interventional sialendoscopy under local anesthesia. Ductal stenosis was the most common feature identified by endoscopy. Among the 12 patients, swelling occurred in 91.7%. Compared with the preoperative score of 6, the mean VAS score 6 months after sialendoscopy was 3; 15 glands (78.9%) showed improved uptake and excretion by SGS. The postoperative VAS score was significantly lower than the preoperative VAS score (P < .05), and the postoperative SGS result was significantly higher than the preoperative SGS result (P < .05). CONCLUSIONS: Interventional sialendoscopy could be an effective technique for the treatment of sialadenitis caused by radioactive iodine.

Evaluation of protective effect of propolis on parotid salivary glands in gamma-irradiated rats.

OBJECTIVE AND BACKGROUND: One of the most significant side effects of radiotherapy for head and neck cancers is xerostomia as a result of salivary gland damage. Considering pharmaco- logical effects of propolis, we evaluated its protective effect on salivary glands subjected to radiotherapy of head and neck cancer patients. MATERIALS AND METHODS: Twenty-one male albino rats (8-11 W, 190 ± 5 gm) were divided into three groups of seven animals. Scintigraphy was performed in all the groups. Then groups 1 (S) and 2 (SR) received normal saline injections and group 3 (PR) received propolis injection over 3 days. After that groups 2 and 3 were exposed to gamma radiation and all the rats underwent scintigraphic assessment on third day and 70th day after irradiation. The lips and tongues of rats in groups 2 and 3 were examined for mucositis daily in first 10 days. At the end, the parotid glands of all rats were examined histologically. RESULTS: Scintigraphy results of third and 70th day after irradiation showed statistically significant differences between PR and SR as well as SR and S. However, there was no significant difference between the PR and S groups. Histopathologic assessment demonstrated significant difference between SR, PR and S. CONCLUSION: These results suggest that propolis has protective effects on salivary gland function in animal models whilst it did not prevent radiation-induced histologic changes in tissues. Further investigations are needed to elucidate mechanisms of propolis actions. Clinical significance: Regarding to the results of this study, propolis may be useful in reduction xerostomia due to radiation to salivary glands and may be helpful for head and neck cancer patients.

Sialoadenitis secondary to ¹³¹I therapy for well-differentiated thyroid cancer.

Radioiodine (¹³¹I) is an important therapy for patients who have well-differentiated thyroid cancer. However, ¹³¹I may also result in side effects in multiple organs and glands. The glands that are frequently affected are the salivary glands with the major untoward effects including sialoadenitis and increased risk of second primary malignancy. This report will review sialoadenitis secondary to ¹³¹I therapy including (1) proposed mechanisms, (2) incidence and clinical presentations, (3) possible approaches to improve prevention, (4) management, and (5) sequelae of sialoadenitis (e.g. xerostomia and salivary duct obstruction). A discussion of second primary malignancies is beyond the scope of this review. With a better understanding of the above, dentists, oral surgeons, otolaryngologists, endocrinologists, nuclear medicine physicians, and nuclear radiologists will be more likely to implement more effective preventive measures to reduce the incidence and severity of ¹³¹I-induced sialoadenitis, and if it does occur, to identify and treat sialoadenitis sooner, thereby potentially reducing not only the severity of the initial symptoms, but also the severity of subsequent sequelae.

Sialographic Analysis of Radioiodine-Associated Chronic Sialadenitis.

OBJECTIVES/HYPOTHESIS: To apply a novel sialography classification system to identify parotid and submandibular ductal findings following I-131 therapy and to assess correlates to dose and duration of symptoms. STUDY DESIGN: Retrospective single-center case series. METHODS: Patients who underwent sialography between February 2008 and February 2019 after previously receiving I-131 treatment were identified via a retrospective chart review. Their sialograms were systematically evaluated and scored by applying the Iowa parotid sialogram scale to also include submandibular gland analysis. RESULTS: From 337 sialograms, 30 (five submandibular, 25 parotid) underwent analysis. Ductal stenosis was identified in all sialograms and was graded as moderate (>50%-75%) in 7/30 cases and severe (>75%) in 15/30 cases. The distal (main) duct was narrowed in 23/30 cases. No association was identified between degree of ductal stenosis and I-131 dose (P = .39), age (P = .81), or time from I-131 therapy to sialogram (P = .97). CONCLUSIONS: The Iowa parotid sialogram scale was successfully applied to report abnormalities of the parotid and submandibular ductal system. The most common manifestation of I-131-associated sialadenitis was a severe stenosis within the distal salivary duct. No statistically significant association was found between degree of ductal stenosis and dose of I-131, age, or duration of symptoms. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E1450-E1456, 2021.

Bombesin-like peptide is present in duct cells in salivary glands: studies on normal and irradiated animals.

Bombesin (BN) and its mammalian counterpart gastrin-releasing peptide act as neuroregulatory hormones and tissue-specific growth factors, and have been implicated as peripheral and central satiety-inducing agents. In the present study, the immunohistochemical expression of BN in submandibular, sublingual and parotid glands of rats was examined 10 days after 5 consecutive days with daily doses of 6-8 Gy irradiation. Radioimmunoassay (RIA) methods were also used. Immunoreactive granular structures were observed within duct cells of both controls and irradiated animals. In the parenchyma of irradiated animals, very few nerve fibres showing BN-like immunoreactivity were observed. The RIA analysis showed that the content of BN-like material significantly increased in submandibular and parotid glands in response to irradiation. The results suggest that mainly a non-neural form of BN is detected in the salivary glands in the immunohistochemical analysis. Thus, the immunohistochemical observations suggest that BN-like peptides may be present in the duct system, where they may be constituents of the saliva. The observations of an increase in BN content in response to irradiation are of interest as BN has mitogenic effects, may stimulate secretion and contributes to satiety.

Structural and functional injury in minipig salivary glands following fractionated exposure to 70 Gy of ionizing radiation: an animal model for human radiation-induced salivary gland injury.

This study explored the feasibility of developing an animal model for radiation-induced salivary gland injury with a radiation protocol identical to current clinical practice. Three male Hanford minipigs were subjected to fractionated daily irradiation with a total dose of 70 Gy; structural and functional measures were compared with those of a control group of minipigs. We found that irradiated submandibular and parotid glands were one-third to one-half the gross size of control glands. Whereas no pathologic changes were noted in control glands, irradiated glands consistently demonstrated significant parenchymal loss with extensive acinar atrophy and interstitial fibrosis, enlarged nuclei in remaining acinar cells, and ductal dilatation and proliferation. Stimulated salivary flow was reduced by 81% in irradiated animals compared with preirradiation flow (P <.001); salivary flow in the control group increased by 30% during the same period (P <.001). The observed radiation-induced structural and functional salivary gland changes are comparable in every respect to those observed following irradiation of human salivary glands.

[Structural changes in the granular duct epitheliocytes and terminal areas of the submandibular glands induced by exposure to light and radiation in rats]. / Strukturnye izmeneniia épiteliotsitov granuliarnykh vyvodnykh protokov i kontsevykh otdelov podnizhnecheliustnykh zhelez krys pri vozdeistvii sveta i radiatsii.

This investigation was aimed at the evaluation of radiomodifying effect of round-the-clock light exposure on the salivary glands. The changes of morphometric parameters of granular duct epitheliocytes and acinar cells in rat submandibular glands were analyzed by means of light and electron microscopy after 48 h of light exposure by 3500-lux cool white fluorescent lamps, single 5 Gy whole-body X-irradiation and their combination. Early changes of granular duct epitheliocytes after light and combined exposure were more significant in comparison with those on acinar cells. On the 10-th day after combined irradiation reduction of nucleoli and endoplasmatic reticulum in the duct cells was more pronounced as compared with similar period following light and X-ray irradiation. Long-term morphological changes in the glands after X-ray and combined irradiation were similar. It is concluded that radiation and round-the-clock light exposure act synergistically.

Postoperative radiotherapy in patients with salivary duct carcinoma: clinical outcomes and prognostic factors.

This study sought to investigate the clinical outcome and the role of postoperative radiotherapy for patients with salivary duct carcinoma (SDC) who had undergone surgery and postoperative radiotherapy. We performed a retrospective analysis of 25 SDC patients treated between 1998 and 2011 with surgery and postoperative radiotherapy. The median prescribed dose was 60 Gy (range, 49.5-61.4 Gy). The clinical target volume (CTV) was defined as the tumor bed in four patients, the tumor bed and ipsilateral neck in 14 patients, and the tumor bed and bilateral neck in six patients. Local control (LC), disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and prognostic variables were analyzed with the log-rank test. The 5-year LC, DFS and OS were 67%, 45% and 47%, respectively. Disease recurrence was found in 12 patients: seven as local, four as regional and eight as distant failure. Perineural and lymphovascular invasion was a significant prognostic factor for LC (P = 0.03). Local failure was common, and the presence of local recurrence significantly affected the OS (P < 0.05). We conclude that surgery and postoperative radiotherapy is expected to decrease the risk of local failure and contribute to good prognoses for patients with SDC. It might be advisable to have the CTV include the cranial nerves involved and the corresponding parts of the skull base in cases of pathologically positive perineural invasion.

Radioprotective effect of vitamin E in parotid glands: a morphometric analysis in rats.

The aim of this study was to evaluate the radioprotective effect of vitamin E on rat parotid glands by morphometric analysis. Sixty male rats were divided into 5 groups (n=6): control, in which animals received olive oil solution; olive oil/irradiated, in which animals received olive oil and were irradiated with a dose of 15 Gy of gamma radiation; irradiated, in which animals were irradiated with a dose of 15 Gy gamma radiation; vitamin E, which received α-tocopherol acetate solution; vitamin E/irradiated, which received α-tocopherol acetate solution before irradiation with a dose of 15 Gy gamma rays. Half of the animals were euthanized at 8 h, and the remaining at 30 days after irradiation. Both parotid glands were surgically removed and morphometric analysis of acinar cells was performed. Data were subjected to two-way ANOVA and Tukey's test (α=0.05). Morphometric analysis showed a significant reduction in the number of parotid acinar cells at 30 days in olive oil/irradiated and irradiated groups. In groups evaluated over time a significant reduction was shown at 30 days in olive oil/irradiated and irradiated groups, indicating that ionizing radiation caused tissue damage. The vitamin E/irradiated group presented more acinar cells than the irradiated group, but no statistically significant difference was observed (p>0.05). In conclusion, vitamin E seems to have failed as a radioprotective agent on acinar cells in rat parotid glands.

Rescue of salivary gland function after stem cell transplantation in irradiated glands.

Head and neck cancer is the fifth most common malignancy and accounts for 3% of all new cancer cases each year. Despite relatively high survival rates, the quality of life of these patients is severely compromised because of radiation-induced impairment of salivary gland function and consequential xerostomia (dry mouth syndrome). In this study, a clinically applicable method for the restoration of radiation-impaired salivary gland function using salivary gland stem cell transplantation was developed. Salivary gland cells were isolated from murine submandibular glands and cultured in vitro as salispheres, which contained cells expressing the stem cell markers Sca-1, c-Kit and Musashi-1. In vitro, the cells differentiated into salivary gland duct cells and mucin and amylase producing acinar cells. Stem cell enrichment was performed by flow cytrometric selection using c-Kit as a marker. In vitro, the cells differentiated into amylase producing acinar cells. In vivo, intra-glandular transplantation of a small number of c-Kit(+) cells resulted in long-term restoration of salivary gland morphology and function. Moreover, donor-derived stem cells could be isolated from primary recipients, cultured as secondary spheres and after re-transplantation ameliorate radiation damage. Our approach is the first proof for the potential use of stem cell transplantation to functionally rescue salivary gland deficiency.

Radioprotective Effect of Vitamin E in Parotid Glands: a Morphometric Analysis in Rats

The aim of this study was to evaluate the radioprotective effect of vitamin E on rat parotid glands by morphometric analysis. Sixty male rats were divided into 5 groups (n=6): control, in which animals received olive oil solution; olive oil/irradiated, in which animals received olive oil and were irradiated with a dose of 15 Gy of gamma radiation; irradiated, in which animals were irradiated with a dose of 15 Gy gamma radiation; vitamin E, which received α-tocopherol acetate solution; vitamin E/irradiated, which received α-tocopherol acetate solution before irradiation with a dose of 15 Gy gamma rays. Half of the animals were euthanized at 8 h, and the remaining at 30 days after irradiation. Both parotid glands were surgically removed and morphometric analysis of acinar cells was performed. Data were subjected to two-way ANOVA and Tukey's test (α=0.05). Morphometric analysis showed a significant reduction in the number of parotid acinar cells at 30 days in olive oil/irradiated and irradiated groups. In groups evaluated over time a significant reduction was shown at 30 days in olive oil/irradiated and irradiated groups, indicating that ionizing radiation caused tissue damage. The vitamin E/irradiated group presented more acinar cells than the irradiated group, but no statistically significant difference was observed (p>0.05). In conclusion, vitamin E seems to have failed as a radioprotective agent on acinar cells in rat parotid glands.

O objetivo neste estudo foi avaliar o efeito radioprotetor da vitamina E sobre glândulas parótidas de ratos por meio de análise morfométrica. Sessenta ratos machos foram divididos em cinco grupos: controle, no qual os animais receberam solução de óleo de oliva; óleo de oliva irradiado, em que os animais receberam óleo de oliva e foram irradiados com uma dose de 15 Gy de radiação gama; irradiado, em que os animais foram irradiados com uma dose de 15 Gy de radiação gama; vitamina E, no qual receberam solução de acetato α-tocoferol; vitamina E irradiado, os quais receberam solução de acetato de α-tocoferol antes da irradiação com uma dose de 15 Gy de radiação gama. Metade dos animais foi eutanasiada em 8 h, e o restante aos 30 dias após a irradiação. Ambas as glândulas parótidas foram removidas cirurgicamente e análise morfométrica das células acinares foi realizada. Os dados foram submetidos à Análise de Variância com 2 fatores e teste de Tukey (α=0,05). A análise morfométrica mostrou uma redução significativa no número de células acinares da glândula parótida aos 30 dias nos grupos óleo irradiado e irradiado. Nos grupos avaliados ao longo do tempo uma redução significativa foi mostrada aos 30 dias nos grupos óleo irradiado e irradiado, indicando que a radiação ionizante causou danos teciduais. O grupo vitamina E/irradiado apresentou mais células acinares que o grupo irradiado, mas diferença estatisticamente significante não foi observada. Em conclusão, a vitamina E parece ter fracassado como um agente radioprotetor nas células acinares das glândulas parótidas de ratos.